Methods and compositions of 4-substituted benzoylpiperazine-1-substituted carbonyls as β-catenin/B-cell lymphoma 9 inhibitors

Abstract

In one aspect, the invention relates to 4-substituted benzoylpiperazine-1-substituted carbonyls having a structure represented by a formula: derivatives thereof, and related compounds; synthetic methods for making the compounds; pharmaceutical compositions comprising the compounds; and methods of treating disorders, e.g., various tumors and cancers, associated with β-catenin/BCL9 protein-protein interaction dysfunction using the compounds and compositions. This abstract is intended as a scanning tool for purposes of searching in the particular art and is not intended to be limiting of the present invention.

What is claimed is: 
     
       1. A method for the treatment of a disorder of uncontrolled cellular proliferation associated with a β-catenin/BCL9 dysfunction in a mammal comprising the step of administering to the mammal an effective amount of at least one compound having a structure represented by a formula: 
       
         
           
           
               
               
           
         
         wherein A is —N— or —CR 8 —;
 wherein R 8  is hydrogen, halogen, unsubstituted C1-C3 alkyl, C1-C3 monohaloalkyl, or C1-C3 polyhaloalkyl; 
 
         wherein L 1  is optionally present, and when present, is O, S, or NH; 
         wherein L 2  is optionally present, and when present, is O, S, NR 9 , or —(CR 10a R 10b ) n —;
 wherein n is an integer having the value of 1, 2, or 3; 
 wherein R 9  is hydrogen, unsubstituted C1-C3 alkyl, C1-C3 monohaloalkyl, or C1-C3 polyhaloalkyl; 
 wherein each occurrence of R 10a  and R 10b  is independently hydrogen, unsubstituted C1-C3 alkyl, C1-C3 monohaloalkyl, or C1-C3 polyhaloalkyl; 
 
         wherein each of R 1a  and R 1b  is independently hydrogen, halogen, unsubstituted C1-C3 alkyl, C1-C3 monohaloalkyl, or C1-C3 polyhaloalkyl; 
         wherein each of R 2a , R 2b , and R 2c  is independently hydrogen, halogen, unsubstituted C1-C3 alkyl, C1-C3 haloalkyl, or C1-C3 polyhaloalkyl; 
         wherein R 3  is Cy 3  or Ar 1 ;
 wherein Cy 3  is a C3-C8 cycloalkyl or a C2-C7 heterocycloalkyl; and wherein Cy 3  is substituted with 0, 1, 2, or 3 groups independently selected from halogen, —CN, unsubstituted C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, cyclopropyl, and —CO 2 H; 
 wherein Ar 1  is selected from aryl and heteroaryl, and wherein Ar 1  is substituted with 0, 1, 2, or 3 groups independently selected from halogen, —CN, unsubstituted C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, unsubstituted cyclopropyl, and —CO 2 H; 
 
         wherein R 4  is hydrogen, halogen, unsubstituted C1-C3 alkyl, C1-C3 haloalkyl, or C1-C3 polyhaloalkyl; 
         wherein each occurrence of R 5  is independently selected from hydrogen, unsubstituted C1-C8 alkyl, C1-C8 monohaloalkyl, or C1-C8 polyhaloalkyl; 
         wherein R 6  is C1-C6 aminoalkyl, C1-C6 hydroxyalkyl, or Cy 1 ; and wherein Cy 1  is an amino C3-C8 cycloalkyl, or a C2-C7 heterocycloalkyl comprising at least one oxygen or nitrogen atom; and wherein Cy 1  is substituted 0, 1, 2, or 3 groups independently selected from halogen, unsubstituted C1-C4 alkyl, C1-C4 monohaloalkyl, and C1-C4 polyhaloalkyl; 
         wherein R 7  is H 2 N—(C1-C6 alkyl)-(C═O)—; HO—(C1-C6 alkyl)-(C═O)—; C1-C6 aminoalkyl, C1-C6 hydroxyalkyl, or Cy 2 ; and wherein Cy 2  is a C2-C7 heterocycloalkyl comprising at least one oxygen or nitrogen atom; and wherein Cy 2  is substituted 0, 1, 2, or 3 groups independently selected from halogen, unsubstituted C1-C4 alkyl, C1-C4 monohaloalkyl, and C1-C4 polyhaloalkyl; 
         or a pharmaceutically acceptable salt thereof, 
         wherein the disorder is cancer. 
       
     
     
       2. The method of  claim 1 , wherein the mammal is human; and wherein the human has been identified to have a 1q21 chromosomal abnormality. 
     
     
       3. The method of  claim 1 , further comprising the step of identifying a human in need of treatment of the disorder; and wherein the step of identifying the human in need of treatment of the disorder comprises the steps of:
 (a) obtaining a sample from the human, wherein the sample comprises cells suspected of being associated with the disorder of uncontrolled cellular proliferaton; and 
 (b) determining if the sample comprises cells with a 1q21 chromosomal abnormality. 
 
     
     
       4. The method of  claim 1 , wherein the cancer is selected from breast cancer and colorectal cancer. 
     
     
       5. The method of  claim 1 , wherein the cancer is colorectal cancer.